Method and device for synthesizing 4-hydroxyquinoline-3-formic acid
1. A method for synthesizing 4-hydroxyquinoline-3-formic acid is characterized by comprising the following steps:
condensation reaction of o-nitrobenzoic acid and potassium monoethyl malonate to obtain 3- (2-nitrophenyl) -3-oxo ethyl propionate;
iron powder is used for reacting with the ethyl 3- (2-nitrophenyl) -3-oxopropionate, and the ethyl 3- (2-aminophenyl) -3-oxopropionate is obtained through reduction;
carrying out closed-loop reaction on the ethyl 3- (2-aminophenyl) -3-oxopropionate, DMF-DMA and DMF to obtain 4-hydroxyquinoline-3-ethyl formate;
hydrolyzing the 4-hydroxyquinoline-3-carboxylic acid ethyl ester under alkaline conditions to obtain the 4-hydroxyquinoline-3-carboxylic acid.
2. The method for synthesizing 4-hydroxyquinoline-3-carboxylic acid as claimed in claim 1, wherein the step of obtaining ethyl 3- (2-nitrophenyl) -3-oxopropanoate by condensation reaction of o-nitrobenzoic acid with potassium monoethyl malonate comprises:
taking a first three-neck flask with the capacity of 100mL, putting a magnetic stirrer into the first three-neck flask, and respectively installing a 100 ℃ thermometer, a three-way adapter and a feeding funnel at three ports;
respectively adding the o-nitrobenzoic acid and the acetonitrile into the first three-neck flask, heating while stirring, then adding the N-N-carbonyl diimidazole into the first three-neck flask in batches, and obtaining a reaction solution A after the addition.
3. The method for synthesizing 4-hydroxyquinoline-3-carboxylic acid as claimed in claim 2, wherein the step of obtaining ethyl 3- (2-nitrophenyl) -3-oxopropanoate by condensation reaction of o-nitrobenzoic acid with potassium monoethyl malonate further comprises:
taking a second three-mouth flask with the capacity of 250mL, putting a magnetic stirrer into the second three-mouth flask, respectively installing a 100 ℃ thermometer, a three-way adapter and a feeding funnel at three mouths, respectively adding the potassium monoethyl malonate and the acetonitrile into the second three-mouth flask, heating while stirring, and then adding MgCl2Adding the mixture into the second three-neck flask in batches to obtain reaction liquid B;
stirring the reaction liquid B at the oil bath temperature of 35 ℃, and then naturally cooling the reaction liquid B to 25 ℃;
and when the temperature is reduced to 25 ℃, slowly dripping triethylamine into the reaction liquid B under the stirring state, and stirring after the addition.
4. The method for synthesizing 4-hydroxyquinoline-3-carboxylic acid according to claim 3, wherein the step of slowly adding triethylamine dropwise to the reaction solution B while stirring and stirring after the addition is completed comprises:
and (3) slowly dropwise adding triethylamine into the reaction solution B, and stirring for 30min at 25 ℃ after the addition is finished.
5. The method for synthesizing 4-hydroxyquinoline-3-carboxylic acid as claimed in claim 4, wherein the step of obtaining ethyl 3- (2-nitrophenyl) -3-oxopropanoate by condensation reaction of o-nitrobenzoic acid with potassium monoethyl malonate further comprises:
slowly pouring the reaction liquid A into the second three-neck flask filled with the reaction liquid B to obtain a reaction liquid C, and stirring the reaction liquid C at 25 ℃ for 2 hours;
then taking a 500mL conical flask, filling 100mL of water, pouring the reaction liquid C into the conical flask, quenching the reaction, then adjusting the pH of the reaction liquid C to 4 by using hydrochloric acid, extracting the reaction liquid C for 3 times by using ethyl acetate after most of acetonitrile is removed by using a rotary evaporator, and after 3 times of extraction, adding an aqueous phase and an organic phase into a plate, and using a climbing plate and a TLC plate to show that the substances in the aqueous phase are completely extracted;
the organic phase is then washed with saturated NaHCO3Washing with the aqueous solution twice, and after washing, washing the organic phase twice with saturated NaCl aqueous solution;
and finally, drying the organic phase by using anhydrous sodium sulfate, carrying out spin drying by using a rotary evaporator at the temperature of 50 ℃, weighing after spin drying to obtain light yellow oily liquid, carrying out nuclear magnetic identification on the dried organic phase by using deuterochloro chloroform as a solvent, and determining to obtain the 3- (2-nitrophenyl) -3-oxo ethyl propionate.
6. The method for synthesizing 4-hydroxyquinoline-3-carboxylic acid according to claim 1, wherein the step of reducing ethyl 3- (2-aminophenyl) -3-oxopropionate by reacting iron powder with ethyl 3- (2-nitrophenyl) -3-oxopropionate comprises:
taking a third three-neck flask with the capacity of 100mL, putting a magnetic stirrer into the third three-neck flask, and respectively installing a 100 ℃ thermometer, a spherical condenser pipe with a three-way adapter and a feeding funnel at three ports;
dissolving the ethyl 3- (2-nitrophenyl) -3-oxopropionate in ethanol at 25 ℃, adding the solution into the third three-neck flask, and adding NH4Adding CI into the third three-neck flask, adding water, opening the constant-temperature magnetic stirrer, setting the stirring temperature to be 60 ℃, and heating while stirring;
and when the temperature rises to 60 ℃, adding Fe into the third three-neck flask in batches, setting the temperature of a constant-temperature magnetic stirrer to be 80 ℃ after adding, heating while stirring to obtain a reaction liquid D, and when the temperature of the stirrer rises to 80 ℃, refluxing and stirring the reaction liquid D for 2 hours at the temperature.
7. The method for synthesizing 4-hydroxyquinoline-3-carboxylic acid according to claim 6, wherein the step of reducing ethyl 3- (2-aminophenyl) -3-oxopropionate by reacting iron powder with ethyl 3- (2-nitrophenyl) -3-oxopropionate further comprises:
after the reaction solution D reacts for 2 hours, 1 drop of the reaction solution is diluted by ethyl acetate, then the diluted reaction solution is sucked into an injector, iron powder is filtered out by a filter head, three points are monitored by a TLC point plate and respectively serve as a raw material point, a cross point of the reaction solution and the raw material and a reaction solution point, and the observation is carried out under a dark box type ultraviolet analyzer.
8. The method of claim 7, wherein the step of reducing ethyl 3- (2-aminophenyl) -3-oxopropanoate using iron powder to react with the ethyl 3- (2-nitrophenyl) -3-oxopropanoate further comprises:
preparing a suction filtration device, and padding a layer of diatomite on a Buchner funnel to filter out Fe powder;
pouring the reaction liquid D into the suction filtration device for filtration, and washing the filter cake for 3 times by using ethyl acetate to wash out the target compound remained in the diatomite;
after the filtration is finished, extracting the filtrate for 2 times by using ethyl acetate, after the extraction for 2 times, dotting the water phase and the organic phase on a plate, and using a climbing plate and a TLC plate to show that the content of the water phase is completely extracted;
and drying the extracted organic phase by using anhydrous sodium sulfate, then spin-drying the organic phase by using a rotary evaporator, weighing the organic phase after spin-drying by using the rotary evaporator to obtain a reddish brown oily liquid, and carrying out nuclear magnetic identification on the spin-dried organic phase by using deuterochloro chloroform as a solvent to determine to obtain the 3- (2-aminophenyl) -3-oxopropanoic acid ethyl ester.
9. The synthesis apparatus using the method for synthesizing 4-hydroxyquinoline-3-carboxylic acid according to claim 1, wherein,
including stirring, stirring includes the body of rod, connector, branch and the stirring body, the both ends of connector respectively with the body of rod with branch fixed connection, the transversal arc structural design of personally submitting of connector, the stirring body with branch fixed connection, and be located branch is kept away from the one end of connector, be provided with a plurality of depressed trenches on the stirring body.
Background
The compound containing the 4-hydroxyquinoline ring structure is a very important nitrogen-containing heterocyclic compound, has very wide biological activity, has wide research prospects in the research fields of medicine and pharmacology, agriculture, chemical industry, materials and the like as an intermediate raw material, and is one of hot contents of researches of researchers, wherein the 4-hydroxyquinoline compound is a very important intermediate raw material in medicine research and development.
The existing 4-hydroxyquinoline-3-formic acid has high cost, long reaction time and troublesome post-treatment in the synthesis process.
Disclosure of Invention
The invention aims to provide a method and a device for synthesizing 4-hydroxyquinoline-3-formic acid, and aims to solve the technical problems of high cost, long reaction time and troublesome post-treatment of 4-hydroxyquinoline-3-formic acid in the synthesis process in the prior art.
In order to achieve the above purpose, the synthesis method of 4-hydroxyquinoline-3-carboxylic acid adopted by the invention comprises the following steps:
condensation reaction of o-nitrobenzoic acid and potassium monoethyl malonate to obtain 3- (2-nitrophenyl) -3-oxo ethyl propionate;
iron powder is used for reacting with the ethyl 3- (2-nitrophenyl) -3-oxopropionate, and the ethyl 3- (2-aminophenyl) -3-oxopropionate is obtained through reduction;
carrying out closed-loop reaction on the ethyl 3- (2-aminophenyl) -3-oxopropionate, DMF-DMA and DMF to obtain 4-hydroxyquinoline-3-ethyl formate;
hydrolyzing the 4-hydroxyquinoline-3-carboxylic acid ethyl ester under alkaline conditions to obtain the 4-hydroxyquinoline-3-carboxylic acid.
Wherein the step of carrying out condensation reaction on o-nitrobenzoic acid and malonic acid monoethyl ester potassium salt to obtain 3- (2-nitrophenyl) -3-oxo ethyl propionate comprises the following steps:
taking a first three-neck flask with the capacity of 100mL, putting a magnetic stirrer into the first three-neck flask, and respectively installing a 100 ℃ thermometer, a three-way adapter and a feeding funnel at three ports;
respectively adding the o-nitrobenzoic acid and the acetonitrile into the first three-neck flask, heating while stirring, then adding the N-N-carbonyl diimidazole into the first three-neck flask in batches, and obtaining a reaction solution A after the addition.
Wherein the step of carrying out condensation reaction on o-nitrobenzoic acid and malonic acid monoethyl ester potassium salt to obtain 3- (2-nitrophenyl) -3-oxo ethyl propionate further comprises the following steps:
taking a second three-mouth flask with the capacity of 250mL, putting a magnetic stirrer into the second three-mouth flask, respectively installing a 100 ℃ thermometer, a three-way adapter and a feeding funnel at three mouths, respectively adding the potassium monoethyl malonate and the acetonitrile into the second three-mouth flask, heating while stirring, and then adding MgCl2Adding the mixture into the second three-neck flask in batches to obtain reaction liquid B;
stirring the reaction liquid B at the oil bath temperature of 35 ℃, and then naturally cooling the reaction liquid B to 25 ℃;
and when the temperature is reduced to 25 ℃, slowly dripping triethylamine into the reaction liquid B under the stirring state, and stirring after the addition.
Wherein, in the step of slowly dripping triethylamine into the reaction liquid B under the stirring state, and stirring after the addition is finished:
and (3) slowly dropwise adding triethylamine into the reaction solution B, and stirring for 30min at 25 ℃ after the addition is finished.
Wherein the step of carrying out condensation reaction on o-nitrobenzoic acid and malonic acid monoethyl ester potassium salt to obtain 3- (2-nitrophenyl) -3-oxo ethyl propionate further comprises the following steps:
slowly pouring the reaction liquid A into the second three-neck flask filled with the reaction liquid B to obtain a reaction liquid C, and stirring the reaction liquid C at 25 ℃ for 2 hours;
then taking a 500mL conical flask, filling 100mL of water, pouring the reaction liquid C into the conical flask, quenching the reaction, then adjusting the pH of the reaction liquid C to 4 by using hydrochloric acid, extracting the reaction liquid C for 3 times by using ethyl acetate after most of acetonitrile is removed by using a rotary evaporator, and after 3 times of extraction, adding an aqueous phase and an organic phase into a plate, and using a climbing plate and a TLC plate to show that the substances in the aqueous phase are completely extracted;
the organic phase is then washed with saturated NaHCO3Washing with the aqueous solution twice, and after washing, washing the organic phase twice with saturated NaCl aqueous solution;
and finally, drying the organic phase by using anhydrous sodium sulfate, carrying out spin drying by using a rotary evaporator at the temperature of 50 ℃, weighing after spin drying to obtain light yellow oily liquid, carrying out nuclear magnetic identification on the dried organic phase by using deuterochloro chloroform as a solvent, and determining to obtain the 3- (2-nitrophenyl) -3-oxo ethyl propionate.
Wherein, the step of reducing and obtaining the ethyl 3- (2-aminophenyl) -3-oxopropionate by reacting iron powder with the ethyl 3- (2-nitrophenyl) -3-oxopropionate comprises the following steps:
taking a third three-neck flask with the capacity of 100mL, putting a magnetic stirrer into the third three-neck flask, and respectively installing a 100 ℃ thermometer, a spherical condenser pipe with a three-way adapter and a feeding funnel at three ports;
dissolving the ethyl 3- (2-nitrophenyl) -3-oxopropionate in ethanol at 25 ℃, adding the solution into the third three-neck flask, and adding NH4Adding CI into the third three-neck flask, adding water, opening the constant-temperature magnetic stirrer, setting the stirring temperature to be 60 ℃, and heating while stirring;
and when the temperature rises to 60 ℃, adding Fe into the third three-neck flask in batches, setting the temperature of a constant-temperature magnetic stirrer to be 80 ℃ after adding, heating while stirring to obtain a reaction liquid D, and when the temperature of the stirrer rises to 80 ℃, refluxing and stirring the reaction liquid D for 2 hours at the temperature.
Wherein, the step of reducing and obtaining the ethyl 3- (2-aminophenyl) -3-oxopropionate by reacting iron powder with the ethyl 3- (2-nitrophenyl) -3-oxopropionate further comprises the following steps:
after the reaction solution D reacts for 2 hours, 1 drop of the reaction solution is diluted by ethyl acetate, then the diluted reaction solution is sucked into an injector, iron powder is filtered out by a filter head, three points are monitored by a TLC point plate and respectively serve as a raw material point, a cross point of the reaction solution and the raw material and a reaction solution point, and the observation is carried out under a dark box type ultraviolet analyzer.
Wherein, the step of reducing and obtaining the ethyl 3- (2-aminophenyl) -3-oxopropionate by reacting iron powder with the ethyl 3- (2-nitrophenyl) -3-oxopropionate further comprises the following steps:
preparing a suction filtration device, and padding a layer of diatomite on a Buchner funnel to filter out Fe powder;
pouring the reaction liquid D into the suction filtration device for filtration, and washing the filter cake for 3 times by using ethyl acetate to wash out the target compound remained in the diatomite;
after the filtration is finished, extracting the filtrate for 2 times by using ethyl acetate, after the extraction for 2 times, dotting the water phase and the organic phase on a plate, and using a climbing plate and a TLC plate to show that the content of the water phase is completely extracted;
and drying the extracted organic phase by using anhydrous sodium sulfate, then spin-drying the organic phase by using a rotary evaporator, weighing the organic phase after spin-drying by using the rotary evaporator to obtain a reddish brown oily liquid, and carrying out nuclear magnetic identification on the spin-dried organic phase by using deuterochloro chloroform as a solvent to determine to obtain the 3- (2-aminophenyl) -3-oxopropanoic acid ethyl ester.
The invention also provides a synthesis device adopting the synthesis method of 4-hydroxyquinoline-3-formic acid, which comprises a stirring piece, wherein the stirring piece comprises a rod body, a connecting body, a supporting rod and a stirring body, the two ends of the connecting body are respectively and fixedly connected with the rod body and the supporting rod, the cross section of the connecting body is in an arc-shaped structural design, the stirring body is fixedly connected with the supporting rod and is positioned at one end of the supporting rod, which is far away from the connecting body, and a plurality of concave grooves are formed in the stirring body.
According to the method and the device for synthesizing the 4-hydroxyquinoline-3-formic acid, disclosed by the invention, a route for synthesizing a target compound, namely the 4-hydroxyquinoline-3-formic acid, is obtained by taking the o-nitrobenzoic acid as a raw material through a condensation reaction, an iron powder reduction reaction, a ring-closing reaction and an ester hydrolysis reaction. The route has the advantages of low raw material price, short reaction time, simple equipment and easier post-treatment.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.
FIG. 1 is a flow chart of the steps of the method of synthesizing 4-hydroxyquinoline-3-carboxylic acid of the present invention.
FIG. 2 is a reaction scheme for the synthesis of ethyl 3- (2-nitrophenyl) -3-oxopropionate according to the invention.
FIG. 3 is a hydrogen spectrum of ethyl 3- (2-nitrophenyl) -3-oxopropionate according to the present invention.
FIG. 4 is a reaction scheme for the synthesis of ethyl 3- (2-aminophenyl) 3-oxopropionate according to the invention.
FIG. 5 is a hydrogen spectrum of ethyl 3- (2-aminophenyl) 3-oxopropionate according to the present invention.
FIG. 6 shows a reaction scheme for synthesizing 4-carbonyl quinoline-3-carboxylic acid ethyl ester according to the present invention.
FIG. 7 is a LC-MS spectrum of ethyl 4-carbonyl quinoline-3-carboxylate according to the present invention.
FIG. 8 is a hydrogen spectrum of ethyl 4-carbonyl quinoline-3-carboxylate according to the present invention.
FIG. 9 shows a reaction scheme for synthesizing 4-hydroxyquinoline-3-carboxylic acid according to the present invention.
FIG. 10 is a LC-MS spectrum of 4-hydroxyquinoline-3-carboxylic acid according to the present invention.
FIG. 11 is an HPLC chromatogram of 4-hydroxyquinoline-3-carboxylic acid of the present invention.
FIG. 12 is a hydrogen spectrum of 4-hydroxyquinoline-3-carboxylic acid according to the present invention.
FIG. 13 is a scheme showing the molecular synthesis of 4-hydroxyquinoline-3-carboxylic acid according to the present invention.
FIG. 14 is a schematic structural view of a 4-hydroxyquinoline-3-carboxylic acid synthesizing apparatus according to the present invention.
1-rod body, 2-connector, 3-support rod, 4-stirring body and 5-concave groove.
Detailed Description
Reference will now be made in detail to embodiments of the present invention, examples of which are illustrated in the accompanying drawings, wherein like or similar reference numerals refer to the same or similar elements or elements having the same or similar function throughout. The embodiments described below with reference to the drawings are illustrative and intended to be illustrative of the invention and are not to be construed as limiting the invention.
Referring to fig. 1 to 13, the present invention provides a method for synthesizing 4-hydroxyquinoline-3-carboxylic acid, comprising the following steps:
s1: condensation reaction of o-nitrobenzoic acid and potassium monoethyl malonate to obtain 3- (2-nitrophenyl) -3-oxo ethyl propionate;
s2: iron powder is used for reacting with the ethyl 3- (2-nitrophenyl) -3-oxopropionate, and the ethyl 3- (2-aminophenyl) -3-oxopropionate is obtained through reduction;
s3: carrying out closed-loop reaction on the ethyl 3- (2-aminophenyl) -3-oxopropionate, DMF-DMA and DMF to obtain 4-hydroxyquinoline-3-ethyl formate;
s4: hydrolyzing the 4-hydroxyquinoline-3-carboxylic acid ethyl ester under alkaline conditions to obtain the 4-hydroxyquinoline-3-carboxylic acid.
In the embodiment, o-nitrobenzoic acid is used as a raw material, and is subjected to condensation reaction with ethyl malonate monoethyl salt to obtain ethyl 3- (2-nitrophenyl) -3-oxopropionate, the intermediate is reduced by iron powder to obtain ethyl 3- (2-aminophenyl) -3-oxopropionate, and then is subjected to closed-loop reaction with DMF-DMA and DMF to obtain ethyl 4-hydroxyquinoline-3-carboxylate, and the intermediate is hydrolyzed under alkaline conditions to obtain the final desired product, namely 4-hydroxyquinoline-3-carboxylic acid. The structure of the final product is identified by three detection methods of LC-MS, HPLC and 1H NMR, and the target compound is confirmed to be obtained. Experiments show that the experimental route can synthesize the target molecule 4-hydroxyquinoline-3-formic acid, has low raw material price, short reaction time, simple equipment and easier post-treatment, and is a feasible route for synthesizing the 4-hydroxyquinoline-3-formic acid in organic synthesis.
Further, the step of obtaining the ethyl 3- (2-nitrophenyl) -3-oxopropionate through the condensation reaction of o-nitrobenzoic acid and potassium monoethyl malonate comprises the following steps:
taking a first three-neck flask with the capacity of 100mL, putting a magnetic stirrer into the first three-neck flask, and respectively installing a 100 ℃ thermometer, a three-way adapter and a feeding funnel at three ports;
respectively adding the o-nitrobenzoic acid and acetonitrile into the first three-neck flask, stirring and heating, then adding N-N-carbonyl diimidazole into the first three-neck flask in batches, and obtaining a reaction solution A after the addition is finished;
taking a second three-mouth flask with the capacity of 250mL, putting a magnetic stirrer into the second three-mouth flask, respectively installing a 100 ℃ thermometer, a three-way adapter and a feeding funnel at three mouths, respectively adding the potassium monoethyl malonate and the acetonitrile into the second three-mouth flask, heating while stirring, and then adding MgCl2Adding the mixture into the second three-neck flask in batches to obtain reaction liquid B;
stirring the reaction liquid B at the oil bath temperature of 35 ℃, and then naturally cooling the reaction liquid B to 25 ℃;
and when the temperature is reduced to 25 ℃, slowly dripping triethylamine into the reaction liquid B under the stirring state, and stirring after the addition.
And (2) slowly dripping triethylamine into the reaction liquid B under the stirring state, and stirring after the addition is finished:
and (3) slowly dropwise adding triethylamine into the reaction solution B, and stirring for 30min at 25 ℃ after the addition is finished.
Slowly pouring the reaction liquid A into the second three-neck flask filled with the reaction liquid B to obtain a reaction liquid C, and stirring the reaction liquid C at 25 ℃ for 2 hours;
then taking a 500mL conical flask, filling 100mL of water, pouring the reaction liquid C into the conical flask, quenching the reaction, then adjusting the pH of the reaction liquid C to 4 by using hydrochloric acid, extracting the reaction liquid C for 3 times by using ethyl acetate after most of acetonitrile is removed by using a rotary evaporator, and after 3 times of extraction, adding an aqueous phase and an organic phase into a plate, and using a climbing plate and a TLC plate to show that the substances in the aqueous phase are completely extracted;
the organic phase is then washed with saturated NaHCO3Washing with the aqueous solution twice, and after washing, washing the organic phase twice with saturated NaCl aqueous solution;
and finally, drying the organic phase by using anhydrous sodium sulfate, carrying out spin drying by using a rotary evaporator at the temperature of 50 ℃, weighing after spin drying to obtain light yellow oily liquid, carrying out nuclear magnetic identification on the dried organic phase by using deuterochloro chloroform as a solvent, and determining to obtain the 3- (2-nitrophenyl) -3-oxo ethyl propionate.
In the embodiment, the synthesis of the compound (ii), ethyl 3- (2-nitrophenyl) -3-oxopropionate, uses o-nitrobenzoic acid, potassium monoethylmalonate, and N, N-carbonyldiimidazole as raw materials, and prepares ethyl 3- (2-nitrophenyl) -3-oxopropionate through condensation reaction. As shown in fig. 2.
And taking the first three-mouth flask with the capacity of 100mL, putting a magnetic stirrer in the flask, and respectively installing a 100 ℃ thermometer, a three-way adapter and a feeding funnel at three mouths. To the first three-neck flask, o-nitrobenzoic acid (3.00g,17.95mmol,1eq) and 30mL of acetonitrile were added, the stirring temperature was set at 20 ℃ and the temperature was raised with stirring, and then N-N-carbonyldiimidazole (3.20g,19.75mmol,1.1eq) was added in portions over about 30 minutes, and after completion of the addition, reaction solution A was stirred at 20 ℃ for 4 hours.
And taking the second three-mouth flask with the capacity of 250mL, putting a magnetic stirrer in the flask, and respectively installing a 100 ℃ thermometer, a three-way adapter and a charging funnel at three mouths. Separately, monoethyl malonate potassium salt (15.28g,89.75mmol,5eq), and 60mL acetonitrile were added to the second three-necked flask, the stirring temperature was set at 35 ℃ and the temperature was raised with stirring, and then MgCl was added over about 15min2(1.85g,19.39mmol,1.08eq) was added portionwise to the second three-necked flask. After the addition was completed, reaction solution B was stirred at an oil bath temperature of 35 ℃ for 1 hour. After 1 hour, the stirring was turned off, and the reaction solution was naturally cooled to 25 ℃. When the temperature is reduced to 25 ℃, triethylamine (5.45g,53.85mmol,3eq) is slowly added into the reaction liquid B in a dropwise manner under stirring, during the dropwise addition, white blocks are generated, the reaction liquid becomes turbid, and after the addition, the reaction liquid B is stirred for 30min at 25 ℃.
After the reaction solution A reacted for 4 hours, the solution changed from a cloudy milky liquid to a pale yellow clear liquid. 1 drop of the reaction solution was diluted with Ethyl acetate to 0.5mL, and monitored by TLC (Petroleum ether: Ethyl acetate 2/1) spot plate at three spots, i.e., a raw material spot, an intersection of the raw material and the reaction solution, and a reaction solution spot, and observed under a dark box type uv analyzer, the raw material (Rf ═ 0.3) was completely reacted, and new spots were formed at (Rf ═ 0.4, Rf ═ 0.5).
After the reaction of the reaction solution B was completed, the reaction solution B was a cloudy white liquid. 1 drop of the reaction solution was diluted with Ethyl acetate to 0.5mL, monitored by TLC (Petroleum ether: Ethyl acetate 2/1) spot plate at three spots, i.e., the feed spot, the intersection of the feed and the reaction solution, and the reaction solution spot, and observed under a dark box uv analyzer, it was found that the feed (Rf ═ 0.4) had reacted completely and a new spot was formed at (Rf ═ 0.6).
After the reaction is completed, slowly pouring the reaction solution A into the second three-neck flask filled with the reaction solution B to obtain a reaction solution C, and stirring the reaction solution C at 25 ℃ for 2 hours. After two hours, a 500mL Erlenmeyer flask was filled with 100mL of water, and the reaction solution C was poured into the Erlenmeyer flask and quenched. The reaction mixture C was then adjusted to pH 4 with 3mol/L (90mL) of hydrochloric acid, and after removal of the major portion of the acetonitrile by rotary evaporation, it was extracted 3 times with 100mL portions of ethyl acetate. After 3 extractions, the aqueous and organic phases were spotted on plates, which were then climbed with (Petroleum ether: Ethyl acetate 2/1) and TLC plates showed that the contents of the aqueous phase had been completely extracted. The organic phase was washed twice with 100mL portions of saturated aqueous NaHCO3 solution. After washing was complete, the organic phase was washed twice more with 100mL of saturated aqueous NaCl solution. And finally, drying the organic phase by using anhydrous sodium sulfate, carrying out spin drying by using a rotary evaporator at the temperature of 50 ℃, weighing the dried organic phase after the spin drying to obtain 3.20g of light yellow oily liquid, and carrying out nuclear magnetic identification on the dried organic phase by using deuterochloro chloroform as a solvent to obtain the 3- (2-nitrophenyl) -3-oxopropanoic acid ethyl ester (compound II) with the yield of 78%. The NMR spectrum is shown in FIG. 3.
And the step of reducing the ethyl 3- (2-aminophenyl) -3-oxopropionate by reacting iron powder with the ethyl 3- (2-nitrophenyl) -3-oxopropionate to obtain the ethyl 3- (2-aminophenyl) -3-oxopropionate, wherein the step comprises the following steps:
taking a third three-neck flask with the capacity of 100mL, putting a magnetic stirrer into the third three-neck flask, and respectively installing a 100 ℃ thermometer, a spherical condenser pipe with a three-way adapter and a feeding funnel at three ports;
dissolving the ethyl 3- (2-nitrophenyl) -3-oxopropionate in ethanol at 25 ℃, adding the solution into the third three-neck flask, and adding NH4CI is added into the third three-neck flask, water is added into the third three-neck flask, and the third three-neck flask is beatenStarting a constant-temperature magnetic stirrer, setting the stirring temperature to be 60 ℃, and heating while stirring;
adding Fe into the third three-neck flask in batches when the temperature is raised to 60 ℃, setting the temperature of a constant-temperature magnetic stirrer to be 80 ℃ after the addition, heating while stirring to obtain a reaction liquid D, and stirring the reaction liquid D at the temperature for 2 hours under reflux when the temperature of the stirrer is raised to 80 ℃;
after the reaction solution D reacts for 2 hours, taking 1 drop of reaction solution, diluting the reaction solution with ethyl acetate, sucking the reaction solution into an injector, filtering iron powder by using a filter head, monitoring by using a TLC point plate, and counting three points which are respectively a raw material point, a cross point of the reaction solution and the raw material and a reaction solution point, and observing the reaction solution point under a dark box type ultraviolet analyzer;
preparing a suction filtration device, and padding a layer of diatomite on a Buchner funnel to filter out Fe powder;
pouring the reaction liquid D into the suction filtration device for filtration, and washing the filter cake for 3 times by using ethyl acetate to wash out the target compound remained in the diatomite;
after the filtration is finished, extracting the filtrate for 2 times by using ethyl acetate, after the extraction for 2 times, dotting the water phase and the organic phase on a plate, and using a climbing plate and a TLC plate to show that the content of the water phase is completely extracted;
and drying the extracted organic phase by using anhydrous sodium sulfate, then spin-drying the organic phase by using a rotary evaporator, weighing the organic phase after spin-drying by using the rotary evaporator to obtain a reddish brown oily liquid, and carrying out nuclear magnetic identification on the spin-dried organic phase by using deuterochloro chloroform as a solvent to determine to obtain the 3- (2-aminophenyl) -3-oxopropanoic acid ethyl ester.
The ethyl 3- (2-nitrophenyl) -3-oxopropanoate is reduced by iron powder to prepare ethyl 3- (2-aminophenyl) 3-oxopropanoate (III). As shown in fig. 4.
And taking a third flask with the capacity of 100mL, putting a magnetic stirrer in the third flask, and respectively installing a 100 ℃ thermometer, a spherical condenser pipe provided with a three-way adapter and a feeding funnel at three ports. After dissolving ethyl 3- (2-nitrophenyl) -3-oxopropionate (II) (3.20g,13.50mmol,1eq) in 70mL of ethanol at 25 ℃, the mixture was added to the third three-necked flask, NH4CI (7.22g,135mmol,10eq) was added to the third three-necked flask, 70mL of water was added, the constant-temperature magnetic stirrer was turned on, the stirring temperature was set at 60 ℃ and the temperature was raised with stirring, Fe (2.26g,40.50mmol,3eq) was added to the third three-necked flask in portions for 30min when the temperature was raised to 60 ℃, the temperature of the constant-temperature magnetic stirrer was set at 80 ℃ and the temperature was raised with stirring, and when the temperature of the stirrer was raised to 80 ℃, reaction solution D was stirred under reflux at this temperature for 2 hours.
After the reaction solution D was reacted for 2 hours, 1 drop of the reaction solution was diluted with Ethyl acetate to 0.5mL, and then taken into a 1mL syringe, iron powder was filtered off with a filter head, and monitored by TLC (Petroleum ether: Ethyl acetate 3/1) spot plate, three spots were spotted, namely, a raw material spot, an intersection of the reaction solution and the raw material, and a reaction solution spot, and observed under a dark box type uv analyzer, and it was found that the raw material (Rf ═ 0.5) had reacted completely and a new spot was formed at (Rf ═ 0.2).
A250 ml suction filtration apparatus was prepared and a layer of diatomaceous earth was placed on a Buchner funnel to filter off the Fe powder. The reaction solution D was poured into a suction filtration apparatus and filtered, and the cake was washed 3 times with 20mL portions of ethyl acetate to wash off the target compound remaining in the diatomaceous earth. After filtration was complete, the filtrate was extracted 2 times with 30mL portions of ethyl acetate. After 2 extractions, the aqueous and organic phases were spotted on plates, which were then climbed with (Petroleum ether: Ethyl acetate 3/1) and TLC plates showed that the contents of the aqueous phase had been completely extracted. The extracted organic phase was dried over anhydrous sodium sulfate, and then the organic phase was spin-dried using a rotary evaporator set at 50 ℃ and weighed to obtain 2.82g of a reddish brown oily liquid. And (3) carrying out nuclear magnetic identification on the dried organic phase by using deuterated chloroform as a solvent to determine that the 3- (2-aminophenyl) -3-oxopropanoic acid ethyl ester (compound III) is obtained with the yield of 88%. The NMR spectrum is shown in FIG. 5.
And (3) carrying out closed-loop reaction on the ethyl 3- (2-aminophenyl) -3-oxopropionate (III), DMF-DMA and DMF to obtain the ethyl 4-carbonyl quinoline-3-carboxylate (IV). As shown in fig. 6.
And taking the fourth three-neck flask with the capacity of 100mL, putting a magnetic stirrer in the flask, and respectively installing a 100 ℃ thermometer, a spherical condenser tube and an addition funnel on three necks. Dissolving the compound III, namely the ethyl 3- (2-aminophenyl) -3-oxopropionate (2.82g,13.62mmol,1eq) in 30mL DMF, adding into the fourth three-neck flask, then adding DMF-DMA (4.87g,40.86mmol,3eq), opening a constant-temperature magnetic stirrer, setting the stirring temperature at 80 ℃, heating while stirring, and when the temperature of the stirrer rises to 80 ℃, refluxing and stirring the reaction solution E at the temperature for 12 hours.
After the reaction solution E was reacted for 12 hours, 1 drop of the reaction solution was diluted with Ethyl acetate to 0.5mL, and monitored by TLC (Petroleum ether: Ethyl acetate: 1/1) spot plate, three spots were spotted, i.e., a raw material spot, a reaction solution spot and an intersection of the raw material spot, the reaction solution spot, and the reaction solution spot was observed under a dark box type uv analyzer, and it was found that the raw material (Rf ═ 0.2) had reacted completely and a new spot was formed at (Rf ═ 0.4).
And after the reaction is finished, naturally cooling the reaction liquid E to 20 ℃, and separating out white solids from the reaction liquid in the cooling process. The reaction solution E was filtered using a 250mL suction filtration apparatus, and the cake was washed with a mixture of 30mL of anhydrous ethanol and 30mL of water. After washing, the filter cake was filled into a 100mL single-necked flask and spin-dried using a rotary evaporator set at 50 ℃ and weighed to give a pale yellow solid, 2.50g of crude product.
The crude product was dissolved with a small amount of ethyl acetate and then 5.00g of silica gel powder was added for sample mixing. And (3) after spin-drying the silica gel sample, sending a small gram-sized normal phase to separate and purify, separating by column chromatography (SiO2, Petroleum ether/Ethyl acetate is 30-2/1, and Rf is 0.4), taking back the eluent, filling the eluent into a 3L single port, spin-drying by a rotary evaporator at the temperature of 45 ℃, and weighing to obtain 1.93g of a light yellow solid. Taking a little light yellow solid by using a 1mL centrifuge tube, dissolving the light yellow solid to 0.5mL by using acetonitrile, filling the solution into an MS bottle, and sending LC-MS for compound monitoring; then a little light yellow solid is taken, DMSO is used as a solvent to send nuclear magnetism for structural identification, and the 4-hydroxyquinoline-3-ethyl formate (IV) is determined to be obtained, wherein the yield is 68%, and the purity is 100%. The LC-MS spectrum is shown in FIG. 7, and the nuclear magnetic spectrum is shown in FIG. 8.
The specific steps of hydrolyzing the 4-hydroxyquinoline-3-ethyl formate under an alkaline condition to obtain the 4-hydroxyquinoline-3-formic acid are as follows:
4-carbonyl quinoline-3-carboxylic acid ethyl ester (IV) is hydrolyzed under the alkaline condition to obtain the final desired product 4-hydroxyquinoline-3-carboxylic acid (V). As shown in fig. 9.
And taking a fifth three-mouth flask with the capacity of 100mL, putting a magnetic stirrer in the flask, and respectively installing a 100 ℃ thermometer, a spherical condenser pipe with a three-way adapter and a feeding funnel at three mouths. The compound IV, namely the 4-carbonyl quinoline-3-carboxylic acid ethyl ester (1.92g,8.76mmol,1eq) is dissolved in 33mL of ethanol, then the solution is added into the fifth three-neck flask, and the constant-temperature magnetic stirrer is opened to start stirring. NaOH (1.05g,26.28mmol,3eq) was dissolved in a conical flask containing 11mL of water, and when the NaOH solid was completely dissolved and the solution became clear, an aqueous NaOH solution was added to the fifth three-necked flask and stirred to obtain a reaction solution F, and the stirrer temperature was set to 70 ℃ and when the stirrer temperature was raised to 70 ℃, the reaction solution F was stirred under reflux at this temperature for 5 hours.
After the reaction solution F reacted for 5 hours, 1 drop of the reaction solution was diluted with Ethyl acetate to 0.5mL, and monitored by a TLC (Petroleum ether: Ethyl acetate 3/1) spot plate, where three spots, which are a raw material spot, a reaction solution spot, and a raw material cross point \ reaction solution spot, were observed under a dark box type uv analyzer, and it was found that the raw material (Rf ═ 0.4) had reacted completely and a new spot was formed at (Rf ═ 0.5). The reaction solution F was naturally cooled to 25 ℃ and poured into a conical flask containing 20mL of water to quench the reaction. The reaction solution F was then adjusted to pH 4 with 3mol/l hydrochloric acid, and during the adjustment, the solution became cloudy and a white solid formed. The reaction solution F was filtered through a 250mL suction filtration apparatus, and the filter cake was washed twice with 10mL of water each time. After filtration, the filter cake was placed in a 50mL single-necked flask and dried by spinning at 50 ℃ using a rotary evaporator, and then weighed to obtain 1.65g of a white solid.
The reaction solution F was naturally cooled to 25 ℃ and poured into a conical flask containing 20mL of water to quench the reaction. The reaction solution F was then adjusted to pH 4 with 3mol/l hydrochloric acid, and during the adjustment, the solution became cloudy and a white solid formed. The reaction solution F was filtered through a 250mL suction filtration apparatus, and the filter cake was washed twice with 10mL of water each time. After filtration, the filter cake was placed in a 50mL single-necked flask and dried by spinning at 50 ℃ using a rotary evaporator, and then weighed to obtain 1.65g of a white solid.
The spin-dried white solid was dissolved with a small amount of ethyl acetate, and 3.00g of silica gel powder was added to the solution to mix the sample. The silica gel sample is dried by a rotary evaporator at 50 ℃, then sent to a microgram normal phase for separation and purification, separated by column chromatography (SiO2, Petroleum ether/Ethyl acetate 40-3/1, Rf 0.5), taken back from the eluent, put into a 2L single port, dried by the rotary evaporator at 45 ℃, and weighed to obtain 1.28g of white solid. Taking a little white solid by using a 1mL centrifuge tube, dissolving the white solid to 1mL by using acetonitrile, filling the white solid into 2 MS bottles, filling 0.5mL into each MS bottle, and sending LC-MS and HPLC to monitor the compound; a little white solid is taken out and sent to nuclear magnetism by using DMSO as a solvent for structural identification, and the 4-carbonyl quinoline-3-formic acid (V) is confirmed to be obtained, the yield is 66%, the purity is 97.9%, and the HPLC purity is 96.05%. The LC-MS spectrum is shown in FIG. 10, the HPLC spectrum is shown in FIG. 11, and the nuclear magnetic spectrum is shown in FIG. 12.
Synthesis and characterization of Compound (II):
the synthesis of the ethyl 3- (2-nitrophenyl) -3-oxopropionate (II) is a condensation reaction, which involves three reactions, a reaction solution A is poured into a reaction solution B to obtain a reaction solution C, and a target compound is generated from the reaction solution C. In the reaction liquid A, CDI needs to be added into the reaction liquid in batches, and the change of temperature needs to be observed in the adding process, and the material is added within 25 ℃, so that the phenomenon that the reaction liquid is stored with heat to cause material flushing due to overhigh temperature is avoided. In the reaction solution B, MgCl2The temperature of the reaction solution is required to be added into the reaction solution in batches, the temperature of the reaction solution is changed within 22-28 ℃ during the adding process, the temperature change is observed, and the phenomenon that the reaction solution is stored heat to cause material flushing due to overhigh temperature is avoided. In the reaction liquid C, attention should be paid to the fact that triethylamine needs to be added into the reaction liquid in a dropwise adding mode, the dropwise adding speed is not too high, and when acid is adjusted, attention should be paid to the fact that the peracid is adjusted so as to avoid influencing the generation of the ethyl 3- (2-nitrophenyl) -3-oxopropionate (II).
Synthesis and characterization of compound (iii):
the synthesis of ethyl 3- (2-aminophenyl) 3-oxopropionate (III) is a reaction in which the nitro group on the phenyl ring is reduced to an amino group by iron powder. The reduction of aromatic nitro compounds is an important organic reaction, and at present, a plurality of methods for reducing aromatic nitro compounds exist.
The carbonyl group is not influenced by the reducing agent because of the carbon-carbon double bond on the benzene ring when the nitro group is reduced by the iron powder[16]And the raw materials are easy to obtain, the price is low, the operation is easy, the equipment requirement is low, and the danger coefficient is small, so the iron powder reduction method is selected.
When reducing NO2 from Fe powder, it should be noted that at 60 c, the Fe powder is added in portions over a period of about 15 minutes, and not too quickly to cause a kick-out. The Fe powder is filtered while being hot, if the Fe powder is not filtered while being hot, black precipitate is generated, by-products are increased, and the difficulty of filtering is increased.
Synthesis and characterization of Compound (IV):
the synthesis of the 4-hydroxyquinoline-3-ethyl formate (IV) is a ring-closing reaction, the reaction mechanism is complex, and the reaction is a nucleophilic addition reaction. Firstly, DMF-DMA is attacked by self nitrogen atom to remove a methoxyl anion so as to obtain an active property enhanced nitrogen positive ion intermediate, the newly formed nitrogen positive ion intermediate is attacked by carbanions formed by proton loss of methyl hydrogen of a compound (IV), methanol is removed to obtain enamine, and the enamine reacts with a nucleophilic reagent DMF[17]To obtain 4-carbonyl quinoline-3-carboxylic acid ethyl ester (IV).
Synthesis and characterization of compound (v):
the synthesis of 4-hydroxyquinoline-3-carboxylic acid (V) is an irreversible reaction in which the ester is hydrolyzed under basic conditions to a sodium carboxylate and an alcohol. In the post-treatment process, hydrochloric acid is used for adjusting the pH value, and the sodium carboxylate reacts with acid to obtain the target products of 4-hydroxyquinoline-3-formic acid and sodium chloride. The small glass beaker is used for weighing when sodium hydroxide is weighed in the experimental process, the weighing is rapid so as to prevent the sodium hydroxide from absorbing moisture, a large amount of heat can be released after water is added into the beaker, the small beaker is required to shake or stir continuously to accelerate the dissolution of the sodium hydroxide and dissipate heat, and the small beaker can also be placed into an ice-water bath for heat dissipation.
By combining the research on the synthetic route of the 4-hydroxyquinoline compound, the above route has the defects of high reaction temperature, long reaction time, low product yield, difficult purification, high operation cost and the like. In view of the above, by referring to relevant documents, a route for synthesizing the target compound, 4-hydroxyquinoline-3-carboxylic acid, is obtained by taking o-nitrobenzoic acid as a raw material through a condensation reaction, an iron powder reduction reaction, a ring-closing reaction and an ester hydrolysis reaction. The route has the advantages of low raw material price, short reaction time, simple equipment and easier post-treatment, is a feasible route for synthesizing the 4-carbonyl quinoline-3-formic acid in organic synthesis, and is shown in figure 13.
Referring to fig. 14, the present invention further provides a synthesizing apparatus using the above method for synthesizing 4-hydroxyquinoline-3-carboxylic acid, including a stirring member, where the stirring member includes a rod body 1, a connecting body 2, a supporting rod 3 and a stirring body 4, two ends of the connecting body 2 are respectively fixedly connected to the rod body 1 and the supporting rod 3, a cross section of the connecting body 2 is designed to be an arc-shaped structure, the stirring body 4 is fixedly connected to the supporting rod 3 and is located at one end of the supporting rod 3 away from the connecting body 2, and a plurality of concave grooves 5 are disposed on the stirring body 4.
In this embodiment, when the connecting body 2, the supporting rod 3 and the stirring body 4 extend into the stirring container to stir, the connecting body 2, the supporting rod 3 and the stirring body 4 can enable objects in the stirring container to be mixed more uniformly, and in addition, the arrangement of the concave groove 5 can further improve the stirring effect of the stirring piece.
While the invention has been described with reference to a preferred embodiment, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
